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PMID: 12908853 Published · ppublish English Journal Article Review

Factors affecting the clinical development of cytochrome p450 3A substrates.

Clinical pharmacokinetics ·Vol. 42 ·No. 11 ·2003-00-00 ·Pages 969-84

Gibbs MA, Hosea NA

Abstract

The objective of this review is to evaluate the risks associated with the discovery and development of cytochrome p450 (CYP) 3A substrates. CYP3A is the most abundant p450 enzyme in human liver and is highly expressed in the intestinal tract. The enzyme contributes substantially to metabolism of approximately 50% of currently marketed drugs that undergo oxidative metabolism. As a result, drug-drug interactions involving inhibitors of CYP3A-mediated metabolism can be of great clinical consequence. It is the position of the authors that, because of the factors responsible for the broad substrate specificity of CYP3A, discovery and development of compounds across a large and broad portfolio that are completely devoid of CYP3A metabolism is not feasible. Thus, it is important that scientifically valid approaches to the discovery and development of compounds metabolised by CYP3A be realised. The clinical relevance of CYP3A metabolism is dependent on a multitude of factors that include the degree of intestinal and hepatic CYP3A-mediated first-pass extraction, the therapeutic index of the compound and the adverse event associated with inhibition of CYP3A metabolism. Thus, a better understanding of the disposition of a CYP3A-metabolised compound relative to the projected or observed therapeutic index (or safety margin) can provide ample evidence to support the continued development of a CYP3A substrate. This document will highlight current practices as well as the benefits and risks associated with those practices.

MeSH Terms
Aryl Hydrocarbon Hydroxylases/metabolism Biotransformation/drug effects,physiology Chemical Phenomena Chemistry, Physical Cytochrome P-450 CYP3A Drug Design Humans Oxidoreductases, N-Demethylating/metabolism Risk Assessment/methods Substrate Specificity/drug effects,physiology
Chemicals
Aryl Hydrocarbon Hydroxylases Cytochrome P-450 CYP3A Oxidoreductases, N-Demethylating
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Gibbs Megan A
Clinical Pharmacokinetics and Pharmacodynamics, Pfizer Inc, Groton, Connecticut, USA.
Hosea Natilie A
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Article Info
Journal
Clinical pharmacokinetics
Abbr.
Clin Pharmacokinet
ISSN
0312-5963
DOI
10.2165/00003088-200342110-00003
Published
2003-00-00
Pages
969-84
Language
English
Region
Switzerland
NLM ID
7606849
Subset
IM
External Links
PubMed source DOI: 10.2165/00003088-200342110-00003 View journal details
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